Histamine is a multifunctional chemical transmitter that signals through cell surface receptors that are linked to intracellular pathways via guanine nucleotide binding proteins. This class of cell surface receptors is called G-protein coupled receptors or GPCRs. There are currently three subtypes of histamine receptors that have been defined pharmacologically and have been divided into H1, H2, and H3 classifications (Hill et al. “International Union of Pharmacology, XIII, Classification of Histamine Receptors”, Pharmacol. Rev. (1997) 49(3):253–278). The H1 histamine receptor has been cloned (Yamashita et al. (1991) “Expression Cloning of a cDNA Encoding the Bovine Histamine H1 Receptor”, P.N.A.S., (1991) 88(24):11515–19) and is the target of drugs such as diphenhydramine to block the effects of histamine in allergic responses. The H2 histamine receptor has been cloned (Gantz et al. “Molecular Cloning of a Gene Encoding the Histamine H2 Receptor”, P.N.A.S. (1991) 88(2):429–33) and is the target of drugs such as ranitidine to block the effects of histamine on acid secretion in the stomach. The third subtype of histamine receptor was hypothesized to exist in 1983 (Arrang et al. “Autoinhibition of Brain Histamine Release Mediated by a Novel Class H3 of Histamine 25, Receptor”, Nature (London) (1983) 302(5911):832–7). It is believed to function as a pre-synaptic auto-receptor in histamine containing neurons in the central nervous system and as a pre-synaptic hetero-receptor in non-histamine containing neurons. One of the functions of the H3 receptor is to regulate neurotransmitter release at the pre-synaptic site. Histamine H3 receptors are thus expressed in the central nervous system, but have also been pharmacologically identified in heart, lung, and stomach, and have been hypothesized to exist in other tissues.
To dissect the in vivo role of histamine H3 receptor signaling pathways, a transgenic mouse was generated in the present invention in which the histamine H3 gene was disrupted by homologous recombination and histamine H3 receptor deficient fibroblasts were prepared.